It is well known that during the fertile years of a woman's life the activity of her ovaries occurs in a cyclic fashion. The orderly sequence of events that underlies this cyclical behavior is called the ovarian cycle or, more commonly, the menstrual cycle. During this time, there is remarkable coordination between the physical changes in various organs and hormone secretion. The interplay between morphological and endocrine events is rather complicated. To simplify matters this account of the ovarian cycle will be divided broadly into two sections. First, a description of the physical changes leading up to and following the release of an ovum at mid cycle and, secondly, the changes that follow ovulation. The mechanisms that regulate each half of the cycle will be considered following the descriptions of the physical changes.

At birth the ovary already contains its full complement of gametes

The fundamental functional unit of the ovary is the follicle, indeed the bulk of the ovary is made up of follicles at various stages of development. This may be seen diagrammatically in Fig. 19-9. During fetal life the primordial germ cells of the ovary are laid down and continue theit mitotic proliferation throughout gestation. Mitosis is complete by the time of birth, so at this time a female will possess all the gametes she will ever have. During fetal life, the primordial germ cells are known as oogonia and, once mitosis is complete, the oogonia enter theif first meiotic division and become known as oocytes. They also become surrounded by mesenchymal cells on a basement mem­brane (the basal lamina) to form the primordial follicles. The oocytes arrest in the diplotene of the first meiotic prophase and then remain in this arrested state until signaled to resume further development. This might occur at any time during the reproductive life of a woman.

The pool of primordial follicles established during fetal life is gtadually depleted throughout the years between puberty and the climacteric (menopause) as, each day, follicles are recruited in

a steady trickle to undergo further development. It is believed that 1—4 primordial follicles begin this process each day. During each ovarian cycle a follicle progresses through a series of developmental stages, which include growth and maturation, ovulation, corpus luteum formation and, in the absence of fer­tilization, degeneration. In most women, the menstrual cycle is between 25 and 35 days in length, although wider variations occasionally occur. This represents the time it takes for an ovary to complete one cycle of folhcular activity. If no pregnancy occurs, the cyclical activity is obvious, ending with the occur­rence of menstruation so that one ovarian cycle is completed in the time between successive menstrual periods.

The development of a follicle may conveniently be split up, for the purposes of explanation, into several distinct stages. These stages have names that teflect either the changing struc­ture or function of the follicle. The first half of the cycle consists of the preantral, antral, and preovulatory stages, which are con­cerned with follicular growth and development. Ovulation occurs at mid cycle, after which the collapsed follicle is con­verted to a corpus luteum—a process known as luteinization. During the final stage of the cycle, the corpus luteum involutes and regresses, a process called luteolysis. These events are summarized in Fig. 19-10.

The preantral follicle

Once a primordial follicle has been triggered to recommence development, it undergoes conversion to a preantral follicle (Fig. 19.11a). This involves a considerable increase in diameter from about 20 /xm to 200—400 /Am. The primary oocyte within the follicle also incteases in size to around 120 /Am. During this phase of growth there is an enormous amount of synthetic activ­ity within the oocyte, in otder to load its cytoplasm with the nutrient materials that it will require during its subsequent maturation. The stromal cells surrounding the oocyte divide to form several layers of granulosa cells and secrete a glycoprotein that forms a cell-free region around the oocyte known as the zona

Fig. 19.10 A summary of the principal phases of the ovarian cycle. The top panel shows the

Menstruation sequence of follicular development,

ovulation, and formation of the corpus luteum. The lower part of the figure shows the relationship between the follicular and luteal phases of the cycle in relation to follicular development.

446

19 The physiology of the mole and female reproductive systems

Fig. 19-11 Stages in the development of the ovum. (a)The early preantral follicle; (b) a late preantral follicle; and (c) shows a late antral (or graafian) follicle. Note the proliferation of stromal and granulosa cells and the development of the fluid-filled antrum.

pellucida. In addition, the cells adjacent to the basal lamina mul­tiply and differentiate to form concentric layers around the primary follicle called the theca. The outermost layers of thecal cells are flattened and fibromuscular in nature (the theca externa) while the inner layers are more cuboidal (the theca interna). Figure 19.Hb shows the appearance of the primary follicle by the end of the preantral stage of development.

Very little is known about the factors that control the entry of primordial follicles into the preantral stage. Even the duration of the phase is uncertain, although it is probably around 2 days. The regular recruitment of follicles appears to take place inde­pendently of hormonal control as removal of the anterior pituitary gland has no effect on the process. Towards the end of the preantral stage, however, an event occurs that is crucial for further follicular development. The follicular cells acquire receptors for certain hormones; the granulosa cells develop receptors for estrogens and for pituitary FSH while the thecal cells develop receptors for pituitary LH. This acquisition of hormone sensitivity is a prerequisite for continued folli-

cular development since each subsequent stage is absolutely dependent on hormonal control.

The antral follicle

The continuous trickle of follicles through the hormone-independent preantral stage ensures that at any one time there are always several follicles that have completed their preantral growth and possess the appropriate receptors for gonadotropins and estrogens. Further development depends upon the endocrine status of the body at the time. Provided that there are adequate levels of FSH and LH in the circulation, any follicles with the right receptors enter the next, antral, stage of development. Preantral follicles that do not possess hormone receptors undergo a process of atresia, that is they degenerate and die.

The anterior pituitary gonadotropins FSH and LH convert preantral to antral follicles. The antral stage of development nor­mally lasts for 8—10 days. During this time the granulosa and thecal cell layers continue to increase in thickness. The granulosa cells also start to secrete follicular fluid all around the oocyte. 19.7 The ovarian cycle

447

This fluid forms the antrum which gives the stage its name. Figure 19.11c shows the general appearance of an antral follicle towards the end of this stage. The entire follicle is now much bigger (around 5 mm in diameter) although the oocyte itself remains much the same size (120 /Am). The oocyte, surrounded by a few granulosa cells, is virtually suspended in follicular fluid and remains attached to the main rim of granulosa cells by a thin stalk. A fully developed antral follicle is also known as a graafian follicle.

Under the influence of gonadotropins, the cells of the antral follicle start to secrete large quantities of hormones. Both the granulosa and thecal cells take on the characteristics of steroid-secreting tissue, with many lipid droplets, microtubules, and smooth endoplasmic reticulum. Under the influence of pituitary LH the cells of the theca interna synthesize and secrete the androgens testosterone and androstenedione. They also produce small amounts of estrogen. The granulosa cells, which possess receptors for FSH, appear to respond to this hormone by con­verting androgens to estrogens (particularly estradiol-17/3). The overall result of this secretory activity is a substantial increase in the circulating levels of both androgens and estrogens, though especially the latter during the antral phase of the menstrual cycle. A simplified diagram showing the synthesis of the main sex hormones is given in Box 19.1.

The estrogens secreted at this time seem to exert a significant effect within the follicle itself. As well as converting androgens to estrogens, the granulosa cells of the antral follicle possess receptors for estrogens. The estrogens produced by the follicular cells bind to these receptors and stimulate proliferation of further estrogen-sensitive granulosa cells. There are thus more granulosa cells avail­able for converting androgens to estrogens and this kind of internal potentiation mechanism results in a substantial increase in cir­culating levels of estrogens throughout the antral phase. Indeed, during the final 2-3 days of this stage (around days 10-12 of the overall cycle), estrogen levels rise rapidly (the estrogen surge). A profile of estrogen secretion during the menstrual cycle illustrating this peak is shown in Fig. 19.12. The estrogens secreted during this time have many important actions throughout the repro­ductive tract, which will be discussed later (Section 19-8).

The preovulatory follicle

As the follicle approaches the end of its antral phase of develop­ment, around the time of the estrogen surge, two important events must coincide if the follicle is to progress further and enter the brief but dramatic preovulatory stage. These are:

acquisition of receptors for pituitary LH by the granulosacells; and

a sharp rise in circulating levels of LH.

LH receptors are synthesized in response to pituitary FSH (for which the granulosa cells already possess receptors), and estro­gen. An estrogen surge also seems to be required for the rise in LH secretion.

If an antral follicle is to proceed to the preovulatory stage, with subsequent ovulation at mid cycle, its acquisition of appropriate

Fig. 19.12 The changes in hormone levels during the menstrual cycle, (a) The pattern of secretion shown by the gonadotropins (FSH and LH); (b) the changes in the plasma levels of estradiol-17/3 and progesterone. The solid bar marked 'm' represents the period of menstruation.

receptors must coincide with high circulating gonadotropin levels. Any follicles that do not have LH receptors at this time will become atretic. Therefore, although several primordial follicles begin to develop every day during fertile life, usually only one fol­licle (the so-called dominant follicle) proceeds to ovulation. As a result there is considerable wastage of follicles during each cycle as some follicles undergo atresia at each stage of development.

The preovulatory stage lasts for only about 36 hours but during that time the follicle shows marked changes that cul­minate in rupture of the follicle and release of the oocyte. This is the process of ovulation, which occurs approximately halfway through the menstrual cycle. All the changes that characterize the preovulatory stage are critically dependent upon pituitary gonadotropins, particularly LH.

Soon after the rise in LH output at the start of the pre­ovulatory stage, the oocyte completes its first meiotic division. This culminates in a rather peculiar division in which half the chromosomes but virtually all the cytoplasm is contained within one cell, the secondary oocyte, while the remaining chromo­somes are discarded in the form of the first polar body. Meiosis^448

19 The physiology of the male ond female reproductive systems

then arrests again and the secondary oocyte is ovulated in this stage of development. The mechanism by which LH initiates the recommencement of meiosis is not understood— perhaps it antagonizes the activity of a meiotic inhibitory factor.

During the antral stage, the granulosa cells of the follicle were mainly concerned with converting androgens to estrogens under the influence of pituitary FSH. In the preovulatory stage, LH stimulates these cells to start synthesizing pro­gesterone instead. As a result, estrogen levels begin to fall slightly while progesterone output rises. At the same time, the granulosa cells lose their receptors for FSH and for estrogen.

At ovulation the follicle ruptures and

the secondary oocyte enters the fallopian

tube

By the end of the preovulatory stage of development, the volume of follicular fluid has increased substantially and the oocyte remains attached to the outer rim of granulosa cells by a thin stalk (see Fig. 19-1 lc). At the time of ovulation, under the influence of LH, the cells of the stalk dissociate and the follicle ruptures. The detailed biochemistry of this process is not understood but it is widely suspected that follicular rupture is in some way dependent upon the switch away from estrogen production towards pro­gesterone production that occurs in the granulosa cells just prior to ovulation.

At ovulation, the follicular fluid flows out onto the surface of the ovary,' carrying with it the secondary oocyte with a few sur­rounding cells. The egg mass is swept into the fallopian tube by currents set up by the movements of cilia on the fimbriae of the ostium (see Section 19-8). The first half of the ovarian cycle is now complete.

After ovulation the follicle forms a

corpus luteum which is regulated by

LH from the anterior pituitary

After the departure of the oocyte and follicular fluid, the remain­der of the follicle collapses into the space, and a blood clot forms within the cavity. The postovulatory follicle, therefore, consists of a fibrin core surrounded by collapsed layers of granulosa cells enclosed within the fibrous thecal capsule. This collapsed follicle then undergoes transformation to become a corpus luteum (from the Latin meaning 'yellow body') which, in the event of fer­tilization, will secrete the appropriate balance of steroid hor­mones to ensure implantation and maintenance of the embryo during the early weeks of pregnancy. The second half of the ovarian cycle is often referred to as the luteal phase.

Formation of the corpus luteum is entirely dependent upon the surge of pituitary LH that occurs during the preovulatory

stage and brings about ovulation itself. The factors that maintain the corpus luteum following the steep decline in gonadotropin levels after ovulation are not clear. In some animals, a luteotropic complex of LH, prolactin, and possibly other hormones seems to be important but the situation in the human female is unclear. Normal basal levels of LH may be sufficient for luteal function.

In the first hours following expulsion of the egg from the ovary. the remaining follicular cells undergo the process of luteinization. They enlarge and develop lipid inclusions that give the corpus luteum the yellowish color that gives it its name. The corpus luteum can grow to between 15 and 30 mm in size by about 8 days after ovulation. At this time it is at its peak of secretory capacity. The cells of the corpus luteum contain increased amounts of Golgi apparatus, endoplasmic reticulum, and mitochondrial protein, and they secrete large amounts of progesterone (see Fig. 19-12). Progesterone levels, which showed a small rise just before ovulation, now increase dramatically, from about 1 ng ml"1 to around 6 or 8ngmH. There is also a consider­able amount of estrogen secreted by the corpus luteum and a second estrogen peak is seen around the middle of the luteal phase. By far the dominant steroid at this time is, however, progesterone.

In the absence of fertilization, the

corpus luteum has a finite life

span

If the oocyte which was released at ovulation remains unfertilized, the corpus luteum degenerates after 10—14 days. This process is known as luteolysis. It involves collapse of the luteinized cells, ischemia, and cell death, with a resulting fall in the output of estrogen and progesterone. This rapid decline in steroid out­put is shown in Fig. 19.12. The degenerated corpus luteum leaves a whitish scar within the ovarian stroma which persists for several months. This is known as the corpus albicans (white body).

What brings about degeneration of the

corpus luteum in the absence of

fertilization?

The mechanisms that underlie the regression of the luteal cells after 12 days or so remain unclear. Estrogen has been implicated in the control of luteal regression in humans, for two reasons. First, the start of degeneration does coincide roughly with the estrogen peak seen 6—8 days after ovulation (Fig. 19-12) and, secondly, injections of estrogens given prior to the naturally occurring peak hasten luteal decline. However, an alter­native explanation is that luteolysis simply occurs gradually as gonadotropin support slowly declines during the luteal phase (Fig. 19.12). 19.8 Hormonal regulation of the female reproductive tract

449

Summary

The first half of the ovarian or menstrual cycle is known as the fol­licular phase and is the period during which a follicle undergoesgrowth and development, culminating in ovulation—rupture of thefollicle and release of the oocyte from the ovary.

A number of follicles start to develop each day but normally onlyone, the dominant follicle, matures to ovulation in each cycle. Theremainder become atretic and die.

The physical changes occurring as the follicle develops are closelyregulated by hormones, particularly the anterior pituitarygonadotropms FSH and LH, and by estrogens produced by thefollicle itself.

The follicular phase may be subdivided into preantral, antral, andpreovulatory stages. The preantral stage of growth lasts for about2 days and appears to be hormone independent. The antral stage,during which considerable further growth occurs, is dependent uponFSH and LH.

Under the influence of FSH and LH, the follicle secretes largeamounts of estrogens. Large amounts of fluid are also secreted by thefollicular cells, so that by the end of the antral stage the oocyte is sus­pended in fluid and attached to the outer rim of follicular cells by athin stalk.

During the preovulatory stage, under the influence of high cir­culating LH levels, the first meiotic division of the oocyte is com­pleted, progesterone secretion begins, and the follicle ruptures torelease the egg mass—ovulation.

The second half of the ovarian cycle, following ovulation, is known asthe luteal phase. The postovulatory follicle is transformed into acorpus luteum under the influence of anterior pituitary LH and theluteal cells change both their structure and function.

The luteal phase is characterized by the secretion of large amountsof progesterone, which has important effects throughout thereproductive tract. Estrogens are also produced.

In the absence of fertilization, the corpus luteum degenerates after10—14 days and steroid output falls to very low levels. This is theprocess of luteolysis, which marks the end of one ovarian cycle.

^19.8 Hormonal regulation of the female reproductive tract

During the follicular phase estrogen

prepares the reproductive tract for

fertilization

The follicular phase of the ovarian cycle is characterized by the secretion of increasing amounts of estrogens. This pattern of estrogen output may be seen in Figs 19.12 and 19.13- Levels of estradiol-17/3 rise gradually during the antral stage of follicular development, reaching 'surge' levels of up to SOOpgml"1 just prior to ovulation (Fig. 19.12). The estrogens secreted during the first half of the cycle perform the crucial task of pre­paring the reproductive tract to receive and transport gametes, and of creating a favorable environment for fertilization and implantation.

Estrogens increase ciliary activity in the fallopian tubes

The influence of ovarian steroidal hormones on the fallopian tubes appears to be quite significant. Removal of the ovaries results in a loss of tubal cilia and a reduction in both secretory and contractile activity of the tubal cells. These effects can be reversed by the sub­sequent administration of estradiol-17/3 and this suggests that estrogens are important for ciliary and muscular activity in the fallopian tubes. This makes sense when one considers the repro­ductive role that the tubes perform. Under the influence of the high levels of estrogens seen in the follicular phase, tubal ciliary and contractile activity is enhanced in preparation for recovering the oocyte from the peritoneal cavity after ovulation and trans­porting it towards the uterus. By the same token, contractile and ciliary activity may help to transport sperm towards the egg.

Estrogens stimulate endometrial

proliferation and increase myometrial

excitability

Both the myometrium and the endometrium of the uterus are extremely sensitive to the ovarian steroids, and the changes in appearance and function occurring in response to these hormones reflect the different roles that the uterus must fulfill during each cycle. The uterus prepares first to receive and transport sperm from the cervix to the fallopian tubes and, later on, to receive and nourish the embryo.

Steroids secreted from the follicular cells act on the uterus to enable it to fulfill these tasks. The estrogens secreted during the follicular phase of the cycle exert a uterotrophic (stimulatory) effect on the endometrium (see Fig. 19.13). As a result, the endometrial stroma proliferates and the surface epithelium increases in surface area; the estrogen-primed epithelial cells secrete a watery fluid. At the same time, the spiral arteries that permeate the stroma start to enlarge. By the time of ovulation the endometrial thickness has increased to around 10 mm (from about 2 or 3 mm just after menstruation). This phase of the endometrial cycle, corresponding to the estrogen-dominated fol­licular phase, is known as the proliferative phase. During this phase the uterus is being prepared to receive a fertilized egg. Estrogens also stimulate the development of progesterone recep­tors on the endometrial cells so that, by the end of the follicular phase, the endometrium is primed to respond to progesterone.

The uterine myometrium is also under the influence of the ovarian hormones. Estrogens appear to increase the excitability of the myometrial smooth muscle and therefore its spontaneous contractility.

Estrogens also affect nonreproductive tissues

The estrogens have widespread and generalized effects through­out the body in addition to those specific actions within the 450

19 The physiology of the male and female reproductive systems

Fig. 19-13 The cyclical changes shown by body temperature, cervical secretions, and the uterine endometrium in relation to the circulating levels of estradiol-17/3 and progesterone.

reproductive tract discussed above. In particular, they exert effects on metabolism and the cardiovascular system:

Estrogens are mildly anabolic and tend to depress theappetite.

They reduce plasma levels of cholesterol, which mayexplain why premenopausal women have a lower risk ofheart attacks than both postmenopausal women and menof comparable age.

They reduce capillary fragility.

Estrogens also appear to have profound effects on moodand behavior but the underlying mechanisms are not clear.

Estrogens cause proliferation of the ductal system of themammary tissue (Chapter 22).

They have important effects on the maintenance of theskeleton (Chapter 23).

Progesterone secreted by the corpus

luteum optimizes conditions for

implantation within the uterus

The uterus houses the embryo for the entire period of its development (gestation). There are two elements to this task:

the endometrial layer must permit implantation of thenewly fertilized egg and subsequently must participate inthe formation of the placenta (placentation); and

the myometrium must remain quiescent during gestationto guard against premature expulsion of the fetus.

Progesterone plays a key role in each of these elements. ^Indeed, adequate levels of progesterone are essential throughout the entire period of gestation to ensure a successful outcome.

During the follicular phase of the cycle, estrogen, secreted by the antral follicle, brings about proliferation of the uterine endometrium along with an increase in the number of glandular structures (see above). Estrogen also stimulates the acquisition of progesterone receptors by the cells of the endometrium. As pro­gesterone levels rise during the luteal phase, the stromal pro­liferation continues and the spiral arteries develop fully. In the event of pregnancy, the spiral arteries will form the blood supply to the maternal side of the placenta. The endometrial glands start to secrete a thick fluid, rich in sugars, amino acids, and glyco-protein, and for this reason this second half of the uterine cycle is often referred to as the secretory phase, and coincides with the luteal phase of the ovarian cycle. All these progesterone-mediated changes help to create a favorable environment for a newly fer­tilized egg and to optimize conditions for implanration and placental formation.

In the absence of a fertilized egg, the corpus luteum regresses after 10—14 days and steroid output falls precipitously (see Figs 19-12 and 19-13). Once the endometrium is deprived of its steroidal support, its elaborate secretory epithelium collapses. The endometrial layers are shed together with blood from the ruptured spiral arteries, which contract to reduce bleeding. This process is known as menstruation. The onset of menstrual bleed­ing is taken to mark the starr of a new ovarian cycle. Contraction of the spiral arteries can lead to the pain experienced by some women at the start of menstruation (dysmenorrhea). Bleeding continues for 3—7 days, during which the total blood loss is between 30 and 200 ml. After this time the endometrial epithelium has been repaired completely.

Progesterone also has a very important effect upon the uterine myometrium. As described earlier, rhe esrrogen-dominated myometrium shows a fair degree of excirability and spontaneous contractility. Clearly, although this may be helpful in assist­ing gamete transporr, it is highly undesirable once an embryo has entered the uterus. Too much excitability could result in spontaneous abortion ('miscarriage') of the fetus. Progesterone tends to relax the smooth muscle of the myometrium, probably by causing hyperpolarization of rhe cell membranes and thereby reduces the likelihood of spontaneous contractions.

Some nonreproductive tissues are influenced by progesterone

Like estrogens, progesterone exerts widespread effecrs through­out the whole body, most of which are poorly understood. For 19,9 Variation of gonadofropins and ovarian steroids during the ovarian cycle

451

example it is a mildly catabolic steroid which stimulates the appetite. Increased levels of progesterone during the luteal phase cause a rise in basal body temperature of 0.2-0.5 °C (see Fig. 19-13). This rise is a useful indicator that ovulation has occurred both for women who are trying to conceive—and for those who are trying not to!

Progesterone promotes development of the lobules and alveoli of the breast (Chapter 22) and causes the breasts to swell as a result of fluid retention by the mammary tissue. This is probably the reason for the breast discomfort experienced by many women during the premenstrual period.

The cervical secretions and vaginal

epithelium show hormone-dependent

cyclical changes

The endocervical glands secrete mucus, the characteristics of which vary considerably during the ovarian cycle. These changes are regulated by the ovarian hormones and have important con­sequences for fertility. Under the influence of the high cir­culating levels of estrogens seen during the follicular phase, the cervical epithelium increases its secretory activity and mucus is produced in large amounts, up to 30 times the quantity secreted in the absence of estrogen (see Fig. 19.1.3). The mucus is thin, watery, and clear and exhibits a characteristic 'ferning' pattern if dried on a slide. It also shows increasing elasticity, and a drop of mucus may be stretched to a length of 10-12 cm. The peak volume and elasticity coincides with the estrogen surge just prior to ovulation. Mucus with these characteristics is most readily penetrated by sperm and this action of estrogen on the cervical glands is a good example of the way in which the endocrine activity of the ovary optimizes the conditions for successful reproduction: when an oocyte is likely to be present, the passage of sperm through the female tract is facilitated.

During the luteal phase, with its high progesterone levels, the mucus is produced in far smaller volumes and becomes much thicker, stickier, and relatively hostile to sperm. It is thus less likely that sperm will reach the uterus and fallopian tubes during the luteal phase. This action of progesterone forms part of the mechanism of action of the progesterone-only contraceptive pill (see also Box 20.1).

The stratified squamous epithelium lining the vagina also changes in appearance in response to the ovarian hormones. Indeed, the histologic appearance of the vaginal epithelial cells may be used as an indicator of the phase of the menstrual cycle reached. In the follicular phase, increased secretion of estrogen stimulates proliferation of the epi­thelial layers. As the superficial layers move farther away from the blood supply they keratinize and many slough off. At mid cycle a vaginal smear will show a preponderance of such cells.

The follicular phase of the ovarian or menstrual cycle is dominated byestrogen secreted by the developing follicle. This estrogen acts withinthe tissues of the reproductive tract to prepare it for gamete trans­port, fertilization, early embryonic development, and implantation.Ciliary and contractile activity in the fallopian tubes is enhanced, theuterine endometrium proliferates, and the glands of the cervix secretelarge volumes of thin, stretchy mucus that is easily penetrated bysperm.

During the second half of the ovarian cycle, the luteal phase, themajor steroid hormone secreted by the corpus luteum is progesterone.Maximum progesterone secretion occurs about 8 days after ovulation.Progesterone prepares the uterus to receive and nourish an earlyembryo in the event of fertilization, and maintains the endometriumin a favorable condition for implantation and placentation.Progesterone also renders the myometrium less excitable, in order toguard against premature expulsion of the embryo.

In the absence of an embryo, the corpus luteum degenerates after10—14 days and steroid output falls steeply. As progesterone levelsfall, the elaborate endometrium which was built up during the cycleis sloughed off and shed, together with blood from the spiral arteries.This process is called menstruation and its onset marks the beginningof a new ovarian cycle.

^19.9 Why do the plasma concentrations of

gonadotropins and ovarian steroids vary during

the ovarian cycle?

The previous sections have focused particularly on the structural and functional changes that occur throughout the 28 days or so that span one complete ovarian cycle. The cyclical alterations in the plasma levels of FSH and LH (shown in Fig. 19-12) are crucial in controlling the cellular and endocrine activity of the ovary; that is, the growth of follicles, the formation of the corpus luteum, and its endocrine activity. How do these fluctuations come about and how do they regulate the follicular cells? In answer to these questions it is important to realize not only that the gonadotropins regulate ovarian function but also that the ovarian steroid hormones themselves, the estrogens and progesterone, in turn influence gonadotropin secretion. This feedback interaction between the anterior pituitary gland, the hypothalamus, and the ovary is illustrated in Fig. 19.14.

The ovarian steroids can exert both negative and positive feedback control on the output of FSH and LH, depending upon the concentration of hormone present and the time for which it has been present. Low or moderare levels of estrogen, particularly estradiol-1 7/3, exert negative feedback on gonado­tropin output, that is they tend to inhibit secretion of FSH and LH. If, however, estrogen is present in high concentrations for several days, the effect switches to one of positive feedback, in which the output of FSH and LH is stimulated. The feed­back actions of progesterone are roughly opposite to those of 452

19 The physiology of the male and female reproductive systems

Fig. 19-14 The positive ( + ) and negative (—) feedback control of the hormonal secretions of the hypothalamus, pituitary gland, and

estrogen. High concentrations of progesrerone inhibit gonadotropin release while low levels appear to enhance the pos­itive feedback effects of estrogens.

The feedback effects of the ovarian steroids are mediated pri­marily at the level of the anterior piruitary itself, probably by alterations in the sensitivity of the gonadotropin-secreting cells to hypothalamic GnRH. There may also be a direct effect of the steroids on GnRH output by the hypothalamic neurons, although this is hard to establish conclusively because of the difficulty in measuring the tiny quantities of GnRH in the portal blood.

The ovarian cycle begins on day 1 of menstruarion. Just prior to this time, levels of both estrogens and progesterone have fallen as the previous corpus luteum declined. Released from the negative feedback inhibition of the ovarian steroids, FSH levels

start to rise slowly, followed shorrly by LH. These events coin­cide with the initiation of the antral phase of follicular develop­ment. Towards the end of the hormone-independent preantral phase, the thecal cells gain receptors for LH while the granulosa cells become responsive to both FSH and estrogens. The coinci­dence of receptor acquisition with steadily rising levels of FSH and LH allows the follicle to enter the hormone-dependent antral phase.

During the preantral and early antral phases of the cycle, ovarian steroid output does not change very much (see Fig. 19-12). Over the next 6—8 days or so, however, estrogen levels rise steadily as the maturing follicle starts to produce large quantities of estrogens under the influence of FSH and LH. During this period, gonadotropin levels themselves remain fairly low as a result of the negative feedback effect of low and moder­ate levels of estrogens. However, this steady rise in estrogen secretion culminates in an estrogen surge during the latter days of the antral phase, when plasma concentrations of estrachol-17/3 reach values between 200 and 400pgmH. This surge of estro­gen secretion initiates important changes in the output of gonadotropins. After about 36 hours, the negative feedback effects of estrogens are replaced by positive feedback which results in a sharp increase in the output of both the gonado­tropins but especially of LH. This constitutes the so-called LH surge which is responsible for the events occurring during the preovulatory phase and for ovulation itself (see Section 19-7).

Once ovulation has taken place, estrogen levels fall sharply as the luteal cells switch to progesterone production. Consequently, the gonadotropins are released from the positive feedback effects of high estrogens, and output of FSH and LH drops as negative feedback reasserts control (see Fig. 19.12). Although estrogen levels may rise to values similar to those seen during the pre­ovulatory surge, this second, luteal, peak fails to elicit a fur­ther LH surge because the high circulating levels of pro­gesterone seem ro block the positive feedback effects of estrogens. Instead, negative feedback continues to predominate and gonadotropin secretion remains low throughout the luteal phase.

In the absence of fertilization, the corpus luteum regresses after 10—14 days and steroid output declines quickly. Deprived of steroid support, the specialized uterine endometrial layers are shed during menstruation. Soon afterwards, FSH and LH levels begin to rise slowly as the anterior pituitary is released from the negative feedback inhibition of estrogens, and a new cycle gets under way as preantral follicles enter the gonadotropin-sensitive antral phase.

The menstrual cycle may be influenced by neural factors

Although the interactions between the ovarian steroids and the pituitary gonadotropins are well documented, and appear to offer a reasonably complete explanation for the cyclical19.10 Puberty and the menopause